Technology: Designer drugs to foil flu virus

A patent published last week in Canberra, Australia, describes a new
class of designer drugs that could treat and prevent the spread of influenza
virus. The compounds appear to block new strains as well as existing ones.
The ability of the flu virus to generate new strains rapidly has been a
major stumbling block for designers of drugs and vaccines against it.

Even people who have recently suffered a bout of flu can be laid low
by new strains. Their immune systems cannot anticipate the changes in the
virus. And despite its trivial, if tiresome, symptoms in healthy people,
flu is a killer of the elderly and people with impaired immune systems.
In 1989, a flu epidemic in Britain killed about 25 000 people.

The new compounds inhibit an enzyme called neuraminidase, which is part
of the flu virus and is essential for it to spread. Flu virus replicates
inside animal cells. New virus particles are transported to the outer surfaces
of the cells, where they are temporarily bound. Neuraminidase acts as a
molecular scalpel, cleaving the bonds and freeing new viruses to infect
other cells.

A small Australian company, Biota Holdings, owns intellectual rights
to the new compounds, but has licensed the British pharmaceutical company
Glaxo to test and develop them commercially.

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The drugs are the result of more than a decade of research by scientists
in Melbourne into the molecular structure of neuraminidase. In the early
1980s, Peter Colman of the CSIRO Division of Biomolecular Engineering in
Melbourne, and Graeme Laver of the Australian National University in Canberra,
succeeded in purifying and crystallising flu neuraminidase.

Colman and George Varghese later worked out the structure of the enzyme
using X-ray crystallography, and identified a pocket-like structure that
is present in all this century’s major strains of flu virus.

Neuraminidase and a second protein, haemagglutinin, are the principal
antigens on the protein coat of the virus that are targeted by the immune
systems of animals. It is when the genes that encode these proteins mutate
that new strains of virus are generated.

The new compounds were specifically designed by chemists at the Victorian
College of Pharmacy in Melbourne to complement the three-dimensional shape
and chemistry of the neuraminidase ‘pocket’. They bind strongly to the enzyme,
preventing it from cutting new virus particles loose.

The patent describes a class of compounds that are all synthetic variants
of neuraminic acid. This compound has been shown to inhibit the action of
neuraminidase in the laboratory but, like other early candidate drugs, either
failed to protect animals against flu, or turned out to be toxic.

Animal trials conducted by Glaxo show the new compounds to be potent
neura-minidase inhibitors and reportedly protected animals against infection.
The patent says that the compounds have low toxicity.

The drugs have yet to be tested in humans but, given their highly selective
activity, Glaxo researchers believe they will prove effective. Glaxo has
developed a nasal spray to deliver the drugs directly to the cells lining
the nasal and respiratory tracts which are targeted by the virus.